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Antibodies with Potent and Broad Neutralizing Activity Against Antigenically Diverse and Highly Transmissible SARS-Cov-2 Variant

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Antibodies with Potent and Broad Neutralizing Activity Against Antigenically Diverse and Highly Transmissible SARS-Cov-2 Variant bioRxiv preprint doi: https://doi.org/10.1101/2021.02.25.432969; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 andDraft is also Manuscript made available: forWang use under et al. a CC02021 license. Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants Lingshu Wang1,†, Tongqing Zhou1,†, Yi Zhang1, Eun Sung Yang1, Chaim A. Schramm1, Wei Shi1, Amarendra Pegu1, Olamide K. Oloninyi1, Amy Ransier1, Samuel Darko1, Sandeep R. 5 Narpala1, Christian Hatcher1, David R. Martinez2,3, Yaroslav Tsybovsky4, Emily Phung1, Olubukola M. Abiona1, Evan M. Cale1, Lauren A. Chang1, Kizzmekia S. Corbett1, Anthony T. DiPiazza1, Ingelise J. Gordon1, Kwanyee Leung1, Tracy Liu1, Rosemarie D. Mason1, Alexandra Nazzari1, Laura Novik1, Adam S. Olia1, Nicole A. Doria-Rose1, Tyler Stephens4, Christopher D. Stringham1, Chloe Adrienna Talana1, I-Ting Teng1, Danielle Wagner1, Alicia T. Widge1, 1 1 1 1 10 Baoshan Zhang , Mario Roederer , Julie E. Ledgerwood , Tracy J. Ruckwardt , Martin R. Gaudinski1, Ralph S. Baric2,3, Barney S. Graham1, Adrian B. McDermott1, Daniel C. Douek1, Peter D. Kwong1, John R Mascola1, Nancy J. Sullivan1,*, John Misasi1,† Affiliations: 15 1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. 2Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. 3Department of Microbiology and Immunology, University of North Carolina School of 20 Medicine, Chapel Hill, NC 27599, USA. 4Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. †Equal contributions *Corresponding author: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.25.432969; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 andDraft is also Manuscript made available: forWang use under et al. a CC02021 license. Abstract: The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive 5 antibodies. We identify four receptor-binding domain targeting antibodies from three early- outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 µg/mL; IC80 < 0.0006 to 0.0251 µg/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that 10 combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs. 15 One Sentence Summary: Ultrapotent antibodies from convalescent donors neutralize and mitigate resistance of SARS-CoV-2 variants of concern. Main Text: Since the start of the SARS-CoV-2 outbreak, >100 million people have been infected and 20 >2 million have died from COVID-19 (1). Shortly after the first Wuhan Hu-1 (WA-1) genome sequence was published (2), spike proteins were generateD for use in spike-specific antibody discovery (3–5). Recently, virus variants first detected in the UK (e.g., B.1.1.7)(6), South Africa (e.g., B.1.351) (7) and Brazil (P.1) (8, 9) have been shown to contain mutations that mediate 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.25.432969; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 andDraft is also Manuscript made available: forWang use under et al. a CC02021 license. resistance to therapeutic monoclonal antibodies, have increased transmissibility and to potentially increase pathogenicity (10–14). Additionally, vaccines designed based on the original WA-1 outbreak strain sequence elicit antibody responses that show decreaseD in vitro neutralizing activity against variants (14–16). In this study, we investigateD antibodies isolated from 5 convalescent subjects who were infected by the WA-1 strain during the first few months of the outbreak, determineD their reactivity against variants of concern (VOCs) and defineD the structural features of their binding to spike. We obtained blood from four mild to moderately ill WA-1-infected subjects between 30 and 50 days after symptom onset. CD19+/CD20+/IgM-/IgA+ or IgG+ B cells were sorteD for 10 binding to S-2P, receptor binding domain-subdomain-1 (RBD-SD1) or the S1 domain and individual B-cell receptors were sequenceD (Figure 1A, Figure S1). In total, we sorted 889 B cells and recovered 709 (80%) paired heavy and light chain sequences and selected 200 antibodies for expression. Among the 200 antibodies, there was a broaD response across all spike domains with 77 binding RBD, 46 binding N-terminal domain (NTD), 58 binding the S2 domain, and 19 binding 15 an indeterminant epitope or failing to recognize spike in a MSD binding assay (Figure 1B). Among these, 4 RBD targeting antibodies, A19-46.1, A19-61.1, A23-58.1 and B1-182.1, were shown to have especially potent pseudovirus neutralization (IC50 0.0025-0.0709 µg/mL) (Figure 1C, E). Live virus neutralization (17) revealed similar high potent neutralization by all four antibodies (IC50 0.0021-0.0048 µg/mL) (Figure 1D-E). All antibody Fabs exhibiteD nanomolar affinity for 20 SARS-CoV-2 S-2P (i.e., 2.3-7.3 nM), consistent with their potent neutralization (Figure 1E). Since VOCs have been reported to contain mutations that confer resistance to RBD- directeD therapeutic antibodies such as LY-CoV555 (18–20), we examined whether the epitopes targeted by the four high-potency antibodies were distinct from LY-CoV555. We used a biolayer 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.25.432969; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 andDraft is also Manuscript made available: forWang use under et al. a CC02021 license. interferometry-based (BLI) competition binding assay to compare the binding profile of these antibodies to LY-CoV555. We noted that while LY-CoV555 prevented the binding of each of the experimental antibodies, the block was not bidirectional; the experimental antibodies did not impact the binding of LY-CoV555. This suggests that these antibodies bind distinct epitopes 5 from LY-CoV555 (Figure 1F). We found that A23-58.1 and B1-182.1 exhibit similar binding profiles and that A19-61.1 and A19-46.1 likewise display a shared binding pattern. However, the latter two antibodies can be distinguished from each other by their capacity to compete for binding with the RBD-targeting antibody S309 (21) (Figure 1F). S309 binds an epitope in RBD that is accessible in the up or down position but does not compete with the SARS-CoV-2 10 receptor protein, angiotensin-converting enzyme (ACE2), and is a Class III RBD antibody (22). To further classify the antibodies, we examined whether these antibodies prevent the binding of ACE2 to spike proteins. We noted that in both BLI-competition and cell surface binding assays, all four experimental antibodies prevented the binding of ACE2 to spike (Figure 1F, Figure S2). This suggests that A19-46.1, A23-58.1 and B1-182.1 neutralize infection by blocking the 15 interaction of RBD with ACE2 and would be classified as either Class I (i.e., ACE2 blocking, binding RBD up only) or II (i.e., ACE2 blocking, binding RBD up or down) RBD antibodies (22). A19-61.1 competes with S309 and blocks ACE2 binding suggesting that it may sterically block ACE2 binding similar to the Class III antibody REGN10987. To refine the classification of these antibodies, we performeD negative stain 3D reconstruction and found that A19-46.1 and 20 A19-61.1 bound near one another with RBD in the down position (Figure 1G), consistent with them being Class II and Class III antibodies, respectively. Similarly, A23-58.1 and B1-182.1 bound to overlapping regions when RBD is in the up position, suggesting that they are Class I antibodies. 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.25.432969; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 andDraft is also Manuscript made available: forWang use under et al. a CC02021 license. Because each donor subject was infected with ancestral WA-1 variants, we evaluated antibody activity against recently emerged variants like D614G, which has become the dominant variant across the worlD (23). We observed that, similar to LY-CoV555, neutralization potency was increased against D614G compared to WA-1, with the IC50 and IC80 of each experimental 5 antibody 1.4 to 6.3-fold lower than that seen for the WA-1 (IC50 of 0.0008-0.0203 µg/mL and IC80 of 0.0026-0.0435 µg/mL) (Figure 2A,C, Figure S3).
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